Magnesium iodide-catalyzed synthesis of 2-substituted quinazolines using molecular oxygen and visible light

Article abstract of DOI:10.1039/c6ra04073j

A novel and efficient approach for the synthesis of quinazolines by aerobic photooxidation with an iodine reagent at room temperature is reported. This method uses harmless visible light from compact fluorescent lamps and molecular oxygen as the sole oxid

Full text of DOI:10.1039/c6ra04073j

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: T. Yamaguchi, K.
Sakairi, E. Yamaguchi, N. Tada and A. Itoh, RSC Adv., 2016, DOI: 10.1039/C6RA04073J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 5
View Article Online
DOI: 10.1039/C6RA04073J
Journal Name
COMMUNICATION
Magnesium iodide-catalyzed synthesis of 2-substituted
quinazolines using molecular oxygen and visible light
Received 00th January 20xx,
Accepted 00th January 20xx
T. Yamaguchi, K. Sakairi, E. Yamaguchi, N. Tada, A. Itoh
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient approach for the synthesis of quinazolines by Thus, the development of more efficient and environmentally
aerobic photooxidation with an iodine reagent at room benign reactions is necessary to realize sustainable, green
temperature is reported. This method uses harmless visible light methods for quinazoline synthesis.
from compact fluorescent lamps and molecular oxygen as a sole
oxidant without the need for a transition-metal catalyst or harsh
reaction conditions.
NH2
NH
condensation
oxidation
N
NH2
+
O
N
R
N
R
H
Nitrogen-containing heterocycles are
a
common and
important structural motif both biologically and industrially.1
Of these heterocycles, quinazolines have been particularly
studied for biological activity and have been reported to
exhibit sedative, anticonvulsant, antitussive, hypotensive, and
antidiabetic properties.2 Consequently, they have been used as
sympatholytic drugs for the treatment of high blood pressure
(Prazosin), non-small cell lung cancer, and pancreatic cancer
(Erlotinib), as well as other conditions (Figure 1).3
— transitionꢀmetal catalyst
— stoichiometric oxidant
— thermal condition
R
H
Scheme 1 Synthesis of quinazolines with 2-aminobenzylamines and aldehydes.
Recently, the use of molecular oxygen instead of other
oxidants has received increasing attention because it is cheap
and represents high atom economy. Thus, novel reactions
using molecular oxygen in the presence of transition-metal
catalysts or organocatalysts have been developed.10
NH2
Our group has previously reported a catalytic cross-
dehydrogenative coupling reaction between tertiary amines
and nucleophiles using molecular oxygen and I2 under visible-
light irradiation.11 This C–C bond forming reaction proceeded
by oxidation of the amines into iminium ions, followed by
addition of the nucleophiles without the need for transition-
metal catalysts or thermal conditions. Therefore, we
envisioned that a novel synthesis of quinazolines could be
achieved by aerobic photooxidation in the presence of
catalytic iodide (Scheme 2). Here we report an efficient
synthetic approach for quinazolines under mild reaction
conditions.
MeO
N
NH
MeO
N
N
O
MeO
MeO
N
N
O
O
O
N
Prazosin
Erlotinib
Figure 1 Drugs containing quinazoline moieties.
Consequently, many approaches for the efficient synthesis
of quinazoline structures have been explored.4 One such
strategy is the condensation of 2-aminobenzylamines and
aldehydes followed by the oxidation of the intermediate
(Scheme 1). However, these reactions require transition-metal
catalysts, such as those based on Cu5 or Ir,6 or stoichiometric
amounts or a large excess of oxidants, such as NaOCl,7 DDQ,8
or MnO2.9 Moreover, harsh reaction conditions are required.
O2, h
ν
O
NH2
cat. iodide
N
R1
R1
+
R2
H
NH2
N
R2
Scheme 2 Synthesis of quinazolines by aerobic photooxidation.
Table 1 shows the results of the optimization of the
reaction conditions. As a result of solvent screening, 2-
phenylquinazoline (3aa) is obtained in moderate yield by
employing ethyl acetate as the solvent (entries 1–4). We then
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 5
View Article Online
DOI: 10.1039/C6RA04073J
COMMUNICATION
Journal Name
Table 2 Scope of aldehydes and 2-aminobenzylaminesa
investigated the effect of the catalyst. This aerobic
photooxidation proceeds with various iodide catalysts, and the
yield increases to 88% when magnesium iodide is used (entries
5–8). The quantity of benzaldehyde required can be reduced
to 1.0 eq. without decreasing the yield (entry 9). Magnesium
iodide is essential for this oxidation system because the
desired product is not formed without catalyst (entry 10).
O2, visible light
MgI2 (5 mol %)
N
NH2
R
R
Ar
+
CHO
EtOAc
N
Ar
N
NH2
1
2
3
N
N
N
N
N
Table 1 Optimization of the reaction conditions
Cl
Br
3aa
3ab
3ac
80% (8 h)
87% (8 h)
83% (8 h)
N
N
N
N
N
N
CO2Me
95% (15 h)
NO2
CN
Entry
Catalyst
Solvent
Hexane
EtOAc
CHCl3
Yield [%]a
3ad
3ae
3af
89% (15 h)
N
94% (15 h)
1
2
I2
0
43
3
N
N
I2
3
I2
N
N
N
4
I2
DMF
5
OMe
Me
t-Bu
Me
5
HI
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
70
26
88
22
89
0
3ag
3ah
3ai
3al
3ao
21% (72 h)
N
93% (20 h)
N
89% (20 h)
6
NaI
Me
N
7
MgI2
OMe
8
Carbon tetraiodide
N
N
N
9b
10b
MgI2
-
3aj
3ak
80% (15 h)
86% (24 h)
N
85% (30 h)
N
N
N
Reaction conditions; 1a (0.3 mmol), 2a (0.45 mmol), and catalyst (5 mol%) in
solvent (5 mL) under O2 atmosphere was stirred and irradiated with a fluorescent
lamp at rt. a 1H NMR yield. b 2a (0.3 mmol) was used.
S
N
Et
N
N
3am
R
3an
96% (20 h)
51% (20 h)
0% (20 h)
With the optimal reaction conditions established, we
investigated the reaction of
1 with various substituted
R = 5ꢀOMe
5ꢀF
61% (24 h)
96% (20 h)
89% (20 h)
86% (24 h)
3ba
3ca
3da
3ea
:
:
:
:
benzaldehydes (Table 2). The corresponding quinazolines are
obtained in excellent yields when an electron-deficient
N
N
6ꢀCl
7ꢀCl
benzaldehyde is employed (3aa–3af). In contrast, the yield
dramatically decreases in the presence of an electron-donating
group such as methoxy at the 4-position of the benzene ring
Reaction conditions; 1 (0.3 mmol), 2 (0.3 mmol), and MgI2 (5 mol%) in EtOAc (5
(
3ag). Reaction with 4-tert-butylbenzaldehyde or 4-
methylbenzaldehyde generates the product in good yield
3ah 3ai). To confirm the effect of steric hindrance, meta- and
mL) under O2 atmosphere was stirred and irradiated with a fluorescent lamp at
rt.
a Isolated yield.
(
–
We then conducted several control experiments to
ortho-substituted benzaldehydes were employed in this
method. It was found that o- and m-tolualdehyde aldehydes
investigate the reaction mechanism. The desired product was
not formed in the absence of molecular oxygen and visible
light irradiation (Scheme 3, equation 1 and 2). 2,2,6,6-
Tetramethylpiperidine-1-oxyl and 2,6-di-tert-butyl-p-cresol,
which are known to be radical scavengers, inhibit the
could
methoxybenzaldehyde is converted to the corresponding
quinazoline in 86% yield (3aj 3al). This suggests that the
be
applied
successfully.
Moreover,
3-
–
electron density at the C2 position is a critical factor in this
oxidation system. Other aldehydes such as 4-
pyridinecarboxaldehyde and 2-thiophenecarboxaldehyde are
oxidized to 3am and 3an, respectively. Unfortunately, no
product is formed when an alkylaldehyde is used as the
substrate (3ao). Furthermore, 4-, 5-, or 6-substituted 2-
aminobenzylamines react with 2a, and the corresponding
generation of 3aa
.
On the other hand, 2,2'-
azobis(isobutyronitrile), which is used to the free radical
generator, does not affect the reaction (Scheme 3, equation
3). Thus, this oxidation system probably proceeds via a radical
process. Next, we investigated whether 4aa is oxidized by
iodine or another active species. When iodine (200 mol%) is
employed as the oxidant in the dark under an argon
atmosphere, the target product is not detected and
dihydroquinazoline is formed in low yield. This result indicates
that oxidation by iodine is not the major pathway in this
reaction.
quinazolines are obtained in good to excellent yields (3ba
–
3ea).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 5
View Article Online
DOI: 10.1039/C6RA04073J
Journal Name
COMMUNICATION
Conclusions
In conclusion, we have developed an efficient synthesis of
quinazolines under aerobic photooxidative conditions. This
novel reaction is interesting as it uses catalytic magnesium
iodide, molecular oxygen as the terminal oxidant, and visible
light from
a general-purpose fluorescent lamp. Further
application and mechanistic study of this reaction are now in
progress in our laboratory.
Notes and references
1
(a) R. Dua, S. Shrivastava, S. K. Sonwane and S. K. Srivastava,
Advan. Biol. Res., 2011, , 120; (b) A. K. Lawrence and K.
Gademann, Synthesis, 2008, 331.
5
2
3
T. P. Selvam and P. V. Kumar, Research in Pharmacy, 2011, 1,
1.
(a) R. Gundla, R. Kazemi, R. Sanam, R. Muttineni, J. A. R. P.
Sarma, R. Dayam and N. Neamati, J. Med. Chem., 2008, 51
,
3367; (b) J. F. Mendes da Silva, M. Walters, S. Al-Damluji and
C. R. Ganellin, Bioorg. Med. Chem., 2008, 16, 7254.
4
(a) A. E. Wendlandt and S. S. Stahl, J. Am. Chem. Soc., 2014,
136, 506; (b) Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X.
Huang and H. Wu, J. Org. Chem., 2013, 78, 11342; (c) T.
Vlaar, R. C. Cioc, P. Mampuys, B. U. W. Maes, R. V. A. Orru
and E. Ruijter, Angew. Chem., Int. Ed., 2012, 51, 13058; (d) S.
Rachakonda, P. S. Pratap and M. V. B. Rao, Synthesis, 2012,
44, 2065; (e) Y. Yan and Z. Wang, Chem. Commun., 2011, 47
,
Scheme 3 Control experiments.
9513; (f) B. Han, C. Wang, R.-F. Han, W. Yu, X.-Y. Duan, R.
Fang and X.-L. Yang, Chem. Commun., 2011, 47, 7818; (g) K.
Karnakar, J. Shankar, S. Narayana Murthy, K. Ramesh and Y.
Scheme 4 shows a plausible mechanism for this reaction,
which is postulated by considering all the above results.
Initially, magnesium iodide is converted to iodine under irradiation
by visible light in an O2 atmosphere, which is followed by
V. D. Nageswar, Synlett, 2011,
Wang, C. Wan and Z. Wang, Chem. Coommun., 2010, 46
8, 1089; (h) J. Zhang, C. Yu, S.
,
5244; (i) J. Zhang, D. Zhu, C. Yu, C. Wan and Z. Wang, Org.
Lett., 2010, 12, 2841; (j) F. Portela-Cubillo, J. S. Scott and J. C.
Walton, J. Org. Chem., 2009, 74, 4934; (k) F. Portela-Cubillo,
J. S. Scott and J. C. Walton, Chem. Commun., 2008, 2935; (l)
S. Ferrini, F. Ponticelli and M. Taddei, Org. Lett., 2007, 9, 69.
B. Han, X.-L. Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen and
W. Yu, J. Org. Chem., 2012, 77, 1136.
J. Fang, J. Zhou and Z. Fang, RSC Adv., 2013, 3, 334.
C. U. Maheswari, G. S. Kumar, M. Venkateshwar, R. A.
Kumar, M. L. Kantam and K. R. Reddy, Adv. Synth. Catal.,
2010, 352, 341.
homolysis
tetrahydroquinazoline (4aa), which is formed by condensation
of 2-aminobenzylamine 1a with benzaldehyde 2a), is
converted to a benzyl radical species by single-electron
transfer. The oxidation occurs again, and 2-
of
the
iodine.
2-Phenyl-1,2,3,4-
(
)
(
5
6
7
phenyldihydroquinazoline is obtained. Subsequently, the
desired product (3aa) is formed via oxidation of 5aa in the
same manner. HI is reoxidized to I2 under aerobic
photooxidative conditions; thus the catalytic cycle is
completed.
8
9
J. J. Vanden Eynde, J. Godin, A. Mayence, A. Maquestiau and
E. Anders, Synthesis, 1993, 867.
Y. Peng, Y. Zeng, G. Qiu, L. Cai and V. W. Pike, J. Heterocycl.
Chem., 2010, 47, 1240.
10 For selected recent examples and reviews, see: (a) A. S.-K.
Tsang, A. Kapat and F. Schoenebeck, J. Am. Chem. Soc., 2016,
138, 518; (b) A. Bechtoldt, C. Tirler, K. Raghuvanshi, S.
O2, h
h
I2
2I
MgI2 or 2HI
Warratz, C. Kornhaaβ and L. Ackermann, Angew. Chem., Int.
I
I
NH
Ed., 2016, 55, 264; (c) A. Gonzalez-de-Castro and J. Xiao, J.
Am. Chem. Soc., 2015, 137, 8206; (d) Y. Tan, W. Yuan, L.
NH
Ph
NH2
NH2
+ PhCHO
N
H
Ph
N
H
Gong and E. Meggers, Angew. Chem., Int. Ed., 2015, 54
,
1a
4aa
13045; (e) J. Li, M. J. Lear, Y. Kawamoto, S. Umemiya, A. R.
Wong, E. Kwon, I. Sato and Y. Hayashi, Angew. Chem., Int.
Ed., 2015, 54, 12986; (f) Z. Zhang, Y. Gao, Y. Liu, J. Li, H. Xie,
H. Li and W. Wang, Org. Lett., 2015, 17, 5492; (g) Y. Qin, L.
I
HI
HI
I
Zhang, J. Lv, S. Luo and J.-P. Cheng, Org. Lett., 2015, 17
,
2HI
2I
1469; (h) J. Liu, F. Liu, Y. Zhu, X. Ma and X. Jia, Org. Lett.,
2015, 17, 1409; (i) Q. Huang, X. Zhang, L. Qiu, J. Wu, H. Xiao,
X. Zhang and S. Lin, Adv. Synth. Catal., 2015, 357, 3753; (j) N.
Bagi, J. Kaizer and G. Speier, RSC Adv., 2015, 5, 45983; (k) A.
E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int.
N
N
NH
Ph
N
Ph
N
H
5aa
Ph
N
H
3aa
Scheme 4 Plausible reaction mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 5
View Article Online
DOI: 10.1039/C6RA04073J
COMMUNICATION
Journal Name
Ed., 2011, 50, 11062. (l) J. Piera and J.-E. Bäckvall, Angew.
Chem., Int. Ed., 2008, 47, 3506.
11 T. Nobuta, A. Fujiya, T. Yamaguchi, N. Tada, T. Miura and A.
Itoh, RSC Adv., 2013, 3, 10189.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C6RA04073J
Table of contents
We disclose a novel and efficient synthesis of 2-substituted quinazolines by aerobic photooxidative
reaction catalyzed by magnesium iodide.